A large amount of evidence links brain vascular disorders to cognitive impairment and dementia including Alzheimer's disease (AD). It is believed these defects impair neuronal health and function by restricting transport of nutrients and oxygen to neurons. Additional studies indicate that cerebrovascular dysfunction plays important roles in the pathogenesis of neurodegenerative disorders, a theory also supported by data that the risk of AD increases three fold in stroke patients. Crucial to vascular tissue function and repair is the process of angiogenesis, the generation of new blood vessels from pre-existing vasculature. Angiogenesis is promoted by complex mechanisms including endothelial cell sprouting and plays critical roles in neovascularization, the generation of new blood vessels in damaged tissue. Insufficient angiogenesis in AD brains may represent an important pathogenic mechanism affecting repair of vasculature and leading to neuronal dysfunction. There is now evidence that type 2 diabetes (T2D), a disease also associated with vascular abnormalities in the brain, is a risk factor for dementia. Thus, brain vasculature abnormalities observed in both AD and T2D may provide etiological links between the two disorders. Literature shows that the EphB4/ephrinB2 bidirectional signaling promotes angiogenesis and that the cytoplasmic domain of ephrinB2 is required for this function. Additional reports indicate that endothelial cell sprouting is promoted by angiogenic complexes of Raf-1, Rok-?, and vascular endothelial cadherin (VE- cadherin) and that presenilin1 (PS1) plays important roles in the development, maintenance, and integrity of brain vasculature. Recently, we obtained data that EphB4 stimulates angiogenic complexes between Raf-1, Rok-?, and VE-cadherin and increases sprouting of endothelial cells in vitro in a ?-secretase-dependent manner. In addition, we found that PS1/?-secretase mediates the EphB4-induced cleavage of ephrinB2 and stimulates production of cytoplasmic peptide ephrinB2/CTF2 that regulates cell sprouting. Together, our observations suggest that the PS1/?-secretase system regulates angiogenesis via proteolytic processing of ephrinB2 and production of ephrinB2/CTF2. Here we propose to use animal models to ask whether AD and T2D impair brain neovascularization in response to ischemic injury and whether formation of angiogenic complexes during neovascularization is affected by AD and T2D. In addition, we will examine whether angiogenic complexes in AD and T2D human brains differ from those in normal controls. We will also ask whether peptide ephrinB2/CTF2 promotes neovascularization in vivo and whether it acts as a protective factor against AD- and T2D-linked vascular impairments.